The estrogen receptor belongs to a steroid nuclear receptor, which is a receptor for nuclear transcription factors induced by ligands. The estrogen receptor is an important cytoregulatory protein that plays a vital role in numerous physiological processes through the endogenous estrogen, including the development and maintenance of secondary sexual characteristics in women, the quality of muscle and bone, etc. The endogenous steroidal estrogen is commonly referred to as a female sex hormone, including estradiol. Estradiol is the major steroidal estrogen found in women's serum, which is mainly secreted by the ovary.
The estrogen receptor (ER) includes the receptor subtype ER-α (estrogen receptor alpha) and ER-β (estrogen receptor beta). There are also receptors (ERRs) closely related to the structure of the estrogen receptor, such as ERR-α, ERR-β and ERR-γ. The steroid nuclear receptor plays an important role in the physiological functions of the body, including transport homeostasis in relation to electrolyte and water balance, growth and development, wound healing, fertility, stress response, immune function and cognitive function. Thus, compounds containing modulators (i.e., antagonists, agonists, partial antagonists and partial agonists) that modulate the activity of the steroid nuclear receptor are capable of treating and preventing diseases that are affected by the steroid nuclear receptor activity. For example, the estrogen receptor ER-β exists in tissues such as the brain, bone, immune system, gastrointestinal tract, lung, ovary, endometrium, prostate, vascular system, genitourinary tract, salivary gland, etc. Therefore, the diseases associated with these tissues can be treated by modulators of selective ligand of ER-β receptor. ER-β acts as an antagonist to the ER-α receptor by heterodimerization with the estrogen receptor ER-α. For example, an ER-β receptor agonist can prevent the estrogen receptor ER-α from promoting the proliferation of tumors in prostate cancer and breast cancer tissues.
It is well known that endogenous estrogen has a great influence on the vascular system of premenopausal women and also has a protective effect on the myocardium. Estrogen directly affects the diastolic function of various vascular tissues (i.e., reduces vasoconstriction or vascular tension), reduces systemic vascular resistance, and improves microvascular circulation. Estrogen also reduces vascular cell proliferation and migration, reduces vascular reactivity and viscosity, and slows fibrosis of blood vessels. ER-β receptor agonist may have therapeutic effects on hypertension and various other cardiovascular diseases such as atherosclerosis and congestive heart failure.
ER-β receptor agonist also has antioxidant activity. In the process of oxidative phosphorylation in the body, various unstable molecules such as reactive oxide species, superoxide (O2−) and hydrogen peroxide (H2O2) are produced. These reactive oxygen species can oxidize endogenous macromolecules such as DNA, lipids and proteins thereby causing damage to their functions. The accumulation of this oxidative damage over time can lead to a variety of age-related diseases. For example, neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and various types of cancers, including prostate and colon diseases, vascular diseases such as stroke, and various age-related atherosclerosis. Ascorbic acid (vitamin C), tea polyphenols derived from red wine, and phytoestrogens such as genistein and coumestrol derived from soy products have the function of eliminating active oxygen in the body. ER-β receptor agonist is a polyphenolic compound which has antioxidant activity. Non-steroidal small molecules as ER-β receptor agonists have been reported in many literatures and patents. However, a polyhydroxyphthalazinone compound as a ER-β receptor agonist has not been reported yet.